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Cardiovascular Research 2003 60(2):226-227; doi:10.1016/j.cardiores.2003.09.008
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Transcription factors for ion channels: active or passive players in cardiac remodeling?

Dobromir Dobrev*

Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscher Str 74, 01307 Dresden, Germany

*Tel.: +49-351-458-6279; fax: +49-351-458-6315. Email address: dobrev{at}rcs.urz.tu-dresden.de

Received 4 September 2003; Chronic cardiac disease is associated with structural, mechanical, and electrical remodeling processes that comprise activation of numerous signal transduction pathways [1]. In hypertrophy and heart failure, for instance, electrical remodeling consists of prolongation of the ventricular action potential duration that may be interpreted as an acquired long-QT syndrome and hence may explain the propensity for ventricular arrhythmias. In myocardial biopsies from these patients, the transient outward current Ito is significantly down-regulated and this is associated with a lower expression of mRNA for the corresponding ion channel subunits (in man predominantly Kv4.3, in rat predominantly Kv4.2; Ref. [2]). Despite the clinical relevance of Ito reduction, the molecular mechanisms regulating ion channel expression in cardiac diseases are currently unknown.

Traditionally, a certain number and species of ion channels within the membrane are considered responsible for the cell type-specific shape of the action potential; however, ion channel numbers should be viewed as highly dynamic. Channel expression can be regulated at multiple cellular levels, i.e. mRNA transcription, altered rates of protein translation, posttranslational protein modifications, changes in membrane trafficking and insertion, and phosphorylation of channel proteins. Regulation of transcription requires regulatory factors that activate or suppress gene expression. These transcription factors bind to certain DNA sequences within the promoter region of a gene, for instance to a GATA motif, which is the binding site for the family of GATA-binding proteins [3]. Fine-tuning of the effects GATA transcription factors is achieved by additional transcriptional modifying proteins, e.g. "friend of GATA"-2 (FOG-2; Refs. [4,5]).

In this issue of Cardiovascular Research, Jia and Takimoto [6] ask the question of how the transcription of the Kv4.2 gene is actually regulated. To this end, they isolated and characterized the promoter region for the rat Kv4.2 gene. The three major findings are: (i) a minimum fragment of approximately 200 bp upstream of the translation starting site is essential for driving transcription of rat Kv4.2 both in cardiac and neuronal cells; (ii) transcription of the Kv4.2 gene is activated by GATA-4 (and also GATA-6), and (iii) regulation of GATA-4-activated transcription by FOG-2 is opposite in cardiac and neuronal cells. In myocytes FOG-2 inhibits, in neuronal cells it enhances GATA-4-induced promoter activation. For the former effect, direct interaction of GATA-4 and FOG-2 is required, whereas the enhancing effect of FOG-2 on GATA-4-induced promoter activation does not require direct interactions. The effects of GATA-4 are cell-specific because they were only observed in cardiac myocytes and neuronal cells but not in fibroblasts. They were also specific for Kv4.2 because they were only detected with this channel subunit but not for Kv4.3.

Can these findings improve our understanding of remodeling in cardiac diseases like hypertrophy, heart failure, or arrhythmias? GATA-4 and GATA-6 are expressed in the heart [7] and can be activated by mechanical stretch or cardiac hypertrophy [8,9]. Stretch induces release of norepinephrine, angiotensin-II (Ang-II), and endothelin-1 from cardiomyocytes and is associated with increased GATA-4 binding to DNA [10,11]. On the other hand, overexpression of GATA-4 or GATA-6 promotes cardiac hypertrophy [9]. In this context, it is noteworthy that GATA-4 regulates expression of numerous genes involved in hypertrophy, i.e. {alpha}-myosin heavy chain ({alpha}-MHC), atrial natriuretic factor and brain natriuretic peptide, sodium/calcium exchanger, cardiac troponin-I, AT1 angiotensin receptor, M2 muscarinic receptor and A1-adenosine receptor (reviewed in Ref. [7]).

Consequently, in hypertrophy and heart failure, increased activity of GATA-4 is expected to activate transcription of the Ito channel subunit Kv4.2 according to the data of Jia and Takimoto [6]. However, the opposite findings were reported, i.e. Ito current amplitude and Kv4.2 expression are reduced in rat models of hypertrophy and heart failure [2,12]. Therefore, the small amplitude of Ito associated with hypertrophy could be due to enhanced activity of FOG-2 since this factor reduced the activity of GATA-4 in cardiomyocytes. Such qualitative discrepancy was also observed with GATA activation and reduced {alpha}-MHC mRNA in hypertrophy despite the fact that GATA-4 enhances the {alpha}-MHC promoter [13]. Again, FOG-2-mediated impairment of GATA-4 activity could serve as an explanation.

The situation is even more complicated because FOG-2 can regulate GATA-4 activity depending on cell context. Jia and Takimoto [6] observed depression by FOG-2 of GATA-4-induced promoter activity for Kv4.2 expression in cardiomyocytes but noted enhancement in a neuronal cell line. Such inconsistent consequences of concomitant actions of FOG-2 and GATA-4 were also observed with enhancement of GATA-induced activation of the {alpha}-MHC promoter in COS cells but suppression in cardiac myocytes [13]. Although the down-regulation of Ito in hypertrophy and heart failure may be related to a FOG-2-mediated suppression of GATA activity, other mechanisms cannot be excluded. Future studies are required to determine the expression and activity of GATA-4, GATA-6, and FOG-2 in cardiac pathology and to characterize their impact on Ito phenotype.

An alternative hypothesis for down-regulation of Ito in the presence of hypertrophic stimuli like Ang-II and norepinephrine is related to direct modulation of the transcription machinery by these hormones. Indeed, Zhang et al. [14] showed that treatment of neonatal rat cardiomyocytes with Ang-II or the {alpha}1-adrenoceptor agonist phenylephrine reduces Kv4.3 mRNA to ~50%, although the underlying molecular mechanisms appear to be different. The rapid time course of decline of Kv4.3 mRNA with Ang-II suggested destabilization of the mRNA, whereas the slow response to phenylephrine was considered to be due to inhibition of mRNA transcription. Do the effects of Ang-II and phenylephrine involve activation of cardiac transcription factors? The answer is not known but would provide valuable insight into the mechanism of hormone-induced regulation of ion channel expression.

In conclusion, the study of Jia and Takimoto [6] is undoubtedly an important step in our understanding of ion channel regulation in the heart and opens a possibility of studying the dynamic nature of ion channel expression, including circadian variation of channel density [15]. Provided that the findings are applicable to human tissue, this work constitutes a novel step in identifying therapeutic targets in hypertrophy and heart failure.


   Acknowledgements
 
The author wishes to thank Ursula Ravens for critical discussion. This work was supported by the Deutsche Forschungsgemeinschaft (DO 769/1) and by the MeDDrive-Programme (Medical Faculty, Dresden University of Technology).


   References
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